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EuroMix

Deliverables

Website for EuroMix project

MATIS will develop the project website: development of a multifaceted website with; 1) A public platform with general information about the project’s approach, objectives, results, and methodology 2) A private platform for the partners, where the relevant project documents, drafts, etc. can be presented for consultation and discussion 3) The project web site will be used to support the community of users of the final software for exposure-driven mixture testing e.g. with a glossary of list of terms used on the website and in the tool, explaining the general framework.

Informative posters and booklets/brochures

•Templates for presentations; •Establish a network of stakeholders and liaison with stakeholder group using website, e-newsletters as well as other stakeholder forums and global networks which partners such as WHO, Freshfel, EPA are involved in;Training and spreading of excellence and best practice (see task 10.3); •Promotional material for conferences, workshops, training (poster, presentation and flyer); •Social media (social networking sites, newsgroups, podcasting, etc.);

Report with recommendation for OECD and other international organisations

Based on the tiered testing strategy proposed by the WHO and the integration of the test results of WP2-4 and WP6 for risk assessment purposes, KI and UoO will set criteria and framework for proceeding to higher-tier testing strategy and will provide guidance on how to use the tiered test and risk assessment strategy (deliverable 8.3, M45). Early communication form Ugent on the attitudes of stakeholders is relevant (milestone 8.2). KI will propose test recommendations (deliverable 8.4, M45) on how new mechanism-based testing should be addressed in relation to existing OECD, EFSA, ECHA and/or ECVAM guidelines (see also task 9.2).

Validation of the aggregated model and comparison with USA software

The modelling approach for aggregate exposure implemented in WP 6 will be validated by ANSES and DLO-B. Validation of the software for aggregate exposure assessment is important. The new model for aggregate exposure assessment will be validated in two different ways. First, unit tests will be written to assure the proper working of the code at a low level. These unit tests will simulate data with known outcomes, and check that the software performs adequately. DLO-B will set up simulation studies and will compare model outcomes with the true values behind the simulated data. Secondly, the new software is compared to the standard program for the exposure assessment of pesticides in the US by the EPA, which is DEEM-SHEDS. For the aggregated models ANSES, with the help of DLO-B, will compare the EuroMix model with the model used in the EPA (e.g. SHEDS-Multimedia). ANSES and DLO-B will write a validation report (D7.1, M36)

Report on stakeholder workshop 2

The project will only be truly successful if its outcomes are widely used by relevant stakeholders, and survive beyond the end of the project. Therefore, it is important that the project will deliver results that meet the needs of the stakeholders, and that stakeholders are aware of it. This necessitates continued stakeholder involvement throughout the project. To accomplish this a number of stakeholder activities are planned: The second and final international stakeholder workshop will be held towards the end of the 4th year of the project to disseminate the project results to stakeholders, and facilitate their use of the project outcome. EuroMix will aim to couple the final stakeholder workshop to another relevant event. KI will provide a proceedings of the stakeholder workshop as delierable 10.7.

Scientific paper ready for submission describing biomarker study

The ongoing Human Biomonitoring project, which is a part of the Norwegian Mother and Child Cohort, at NIPH will be used to collect serum (2000 µl), lymphocytes (100 µl) and urine (5 ml) from adults, 70 males and 70 females (in total 140 participants). Serum and urine samples will be used to assess cumulative and aggregated exposure to the selected chemicals in the mixture. A 48 hours diary based on weighing of the consumed food will be performed prior to sample collection, and used together with concentration data in foods for the estimation of exposure. Analytical methods for 3 metabolites of interest in serum and/or urine will be developed to estimate the level of exposure (NIPH). Variability will be studied and estimated exposure will be compared with the levels of biomarkers for exposure in urine or serum. An application for the Human Bio monitoring Project will be sent to the regional committee of medical research ethics and the Data Inspectorate for approval. Participants will be collected and a list of names and ID will be kept locked up and separated from the samples. All participants will have to sign a written approval upon participation and they will be informed that they can withdraw from the study at any time during the study. Upon withdrawal from the study, the biological samples will be destroyed unless included in the scientific work already published. The studies will be carried out according to existing guidance in ethics such as laid down in the Universal Declaration on Bioethics and Human Rights adopted by UNESCO's General Conference on 19 October 2005, the Council of Europe Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine (1997) and as specified in the Helsinki Declaration (2000). NIPH will describe the results and human study in deliverable 7.2 (M45).

Minutes of meetings with Scientific Advisory Board

The coordinator will implement an effective innovation management strategy. RIVM will organize three meetings with the scientific advisory board. The discussions and recommendations of these meetings will be summarised in deliverable 1.3.

Scientific article ready for publication describing the in vivo studies

For the selected toxicological apical endpoints (liver, developmental, endocrine and immuno toxicity) animal experiments will be designed to validate the molecular signatures against toxicological findings in animals, and to verify the CAGs created on the basis of the in-vitro models laid out in WP3 and PB-PK/D models (Task 4.2.). Selection of mixtures will be done in close cooperation with WP3and with WP7, which will validate the overall approach of the EuroMix test strategy. The index compounds will be tested in a benchmark design, with a dose-range, covering both human exposure levels and effect levels (e.g. between the NOAEL and the LOAEL). Other compounds included in the same CAG blased on toxicological consideration will be tested alone or in combination and the dose response curves will be compared with those expected based on the modelling (BMD and/or PB-PK-PD). The choice of the CAG compounds to be tested will be based on several considerations: e.g.: mode of action, target organ/system effect, pesticides contributing most to exposure (as identified in WP5), non-pesticide chemicals that appear to provide the most relevant exposure levels for humans, and other chemicals that may prove useful to serve in a case study for proof-of-principle. Relevant organs and tissues of the treated animals will be examined for morphological, histological, and molecular alterations, as suggested by the in-vitro studies conducted under WP3. The outcome of this analysis will be compared with the predictions made based on the in-vitro studies conducted under WP3. The design of the animal studies will be tailored on the question to be asked, taking advantage of the existing OECD Guidelines for a 28-day study (OECD 407) for liver toxicity, for developmental toxicity (OECD 414), and endocrine and (limited) immuno toxicity (Extended One Generation Reproduction Toxicity, OECD 442). Liver toxicity (BfR): building on the existing data and exposure consideration conazoles will serve as starting CAG for liver toxicity. Developmental toxicity (UMIL and BPI): building on the existing data and exposure consideration conazoles will serve as starting CAG for cranio-facial malformations. Since not all conazoles cause the same phenomenological effects, based on the in vitro studies the most appropriate combination will be chosen. While compounds with dissimilar mode of action might be identified in collaboration with WP2 and WP3; however ethanol and human drugs such as valproic acid might be considered for either exposure (ethanol) or mechanistic/proof-of-principle reasons (valproic acid). Endocrine active substances (URV): Experiments will be conducted for compounds of either natural or man-made origin, and presenting either similar or dissimilar activity, e.g. on the estrogenic system (e.g. genistein, physiological hormones, inhibitors of the synthesis, etc.). A number of key apical developmental hormone–dependent endpoints, such as gonadal function, the oestrous cycle, epididymal sperm maturation, mating behaviour, conception, pregnancy, parturition, and lactation, among others, will be assessed. Immunotoxicity: No specific in-vivo studies will be developed for immune toxicity, but rather that basic immune parameters identified in WP3 are included in the EOGRT study. The results of the in vivo studies will be described in deliverable 4.3 (M48).

Guidance on the use of the new strategy for tiered testing and assessment

KI will perform a literature review of the currently used and proposed approaches to evidence- and risk-based health risk assessment of chemical mixtures. Part of the review will be addressing this framework will be tested for Risk Assessment and Management of Combined Exposure to Multiple Chemicals in Drinking Water and Source Water using available measurement data of relevant substances in tap water (KI and RIVM). CZU, ANSES, URV and MATIS, having access to total diet studies from several countries, will perform an exposure case study in addition to include data from a total diet study (TDS) based on the experience of the EU project Total Diet Study Exposure. The current methodology and the relationship with the new proposed methodology will be described in milestone 8.1. (M12). Based on the tiered testing strategy proposed by the WHO and the integration of the test results of WP2-4 and WP6 for risk assessment purposes, KI and UoO will set criteria and framework for proceeding to higher-tier testing strategy and will provide guidance on how to use the tiered test and risk assessment strategy (deliverable 8.3, M45).

Minutes of meetings with External Advisory Board

The coordinator will also organize three meetings with the External Advisory Board to ensure an optimal fine-tuning with the needs of international risk assessment and risk management institutes. The discussions will be summarised and recommendations will be given n deliverable 1.4.

Scientific article ready for submission describing the case study for aggregated exposure assessment

ETHZ and ANSES will make a database with available data of concentrations in consumer products or non-dietary matrix for the selected endpoints (liver, development and endocrine). The level of aggregated exposure will also be determined by individual habits. ETHZ will overview the availability and usability of that data. Priority will be given to substances in the selected mixtures of task 5.3 and to chemicals mainly present in the diet. ETHZ, ANSES, DEFRA and BfR will make a description of the relevant models developed by ETHZ, RIVM (PACEM), BfR (AOEM), and DEFRA (Browse/Bream) and how they can be connected to the dietary exposure as calculated in task 5.3. ETHZ, ANSES and DEFRA will make a functional design how these models can be implemented in the EuroMix web-based model toolbox and how the models can be linked to dietary exposure. PB-PK models developed in WP4 for the chemicals listed as priority in task 5.3 will be tested to aggregate the exposure from the different sources (dietary and non-dietary) and to estimate internal dose. This will result in a functional design to be implemented in the EuroMix model tool box in milestone WP6. Three case studies will be performed with the selected aggregeted exposure models: (1) A case study conducted by DEFRA and BfR that addresses the operator exposure together with exposure via food (e.g. a mixture of relevant pesticides that has been identified in task 2.1. (2) a case study by ETHZ on perfluorinated compounds (PFAS) to represent environmentally relevant chemicals that are also used in food-contact materials (see also task 3.3), for which hepatotoxic as well as endocrine effects have been reported in vivo, and which therefore belong to the CAGs in the focus of this proposal. (3) a case study by ANSES on for example pyrehroid and bisphenol A mixtures. The results will be reported in scientific article ready for submission deliverable D5.4 (M44).

Scientific article ready for publication describing the method to identify mixtures

ANSES, in cooperation with RIVM, will define exposure scenarios. The scenarios will address the cumulative assessment groups defined by EFSA and based on data organized in task 5.1. ANSES, RIVM, CZU, MATIS, Ugent, HSE, NIJZ, URV, BPI and Ministry of Health of the Republic Cyprus will divide the exposure scenarios and chemicals of interest. Exposure calculations will be performed using probabilistic methods already implemented in the ACROPOLIS-IT tool, which is part of the EuroMix web-based model toolbox. Depending on the nature of the risk (acute or chronic), exposure will be estimated at the person-day or person level, respectively. Acute exposure will be calculated by Monte Carlo integration of consumption and concentration distributions. Chronic exposure will be calculated using the Logistic Normal-Normal (LNN) model. NIJZ, BPI and Ministry of Health of the Republic Cyprus will search for processing factors in the open literature and/or Draft Assessment Reports. The calculations will account for processing effects and unit variability as far as practically possible. This will result a scientific article ready for publication (deliverable 5.1).

Report describing the methodology and results of the refine and retain approach

The combined exposure levels as reported in task 5.2 for the cumulative assessment groups set by EFSA will be used as a starting point. This includes a large number of chemical and a number of chemicals will hardly contribute to the risk. WP3 and WP4 will perform the mixture experiments resulting in more refined information about relative potency factors, dose-addition, mixture endpoints, and information about inclusion or exclusion of chemical in the cumulative assessment groups. Cumulative exposure scenarios will be developed starting from worst-case scenario including all chemicals and working towards including more refined information and addressing only the chemicals significantly contributing to the exposure levels defined in task 5.3. DEFRA will write a report describing the results and how to perform the refine and retain approach. This corresponds to deliverable D5.5, which will be ready in M44.

Report usefulness of the TTC concept for risk assessment of mixtures

This task, to be performed by ICL, BPI, NIPH and HSE aims to use the TTC concept for excluding chemicals from the list of substances initially identified in Task 2.1 (and further adjusted by the in-silico analyses of Task 2.2). More generally, the outcome of this task will also be used to assess the applicability of the TTC approach in a tiered testing strategy for mixtures (in Task 2.4 and WP8). The TTC concept will be applied for the selected endpoints along the principles set out in the EFSA opinion and building on the WHO/IPCS case study published with their framework. The use of TTC values as surrogates for chemical-specific reference values (e.g. acceptable daily intake) in the risk assessment of mixtures will also be investigated. Partner HSE has experience of using TTC in the evaluation of exposures to pesticide metabolites, has produced a technical report for EFSA work on TTC, participated as an ad hoc member of the EFSA PPR panel for TTC discussions, and has been involved in recent initiatives on developing TTC for the future. NIPH has experience in using the TTC principle in risk assessment of flavouring compounds and food contact materials in EFSA risk assessment (Chair WG BPA) and ICL has experience with the use of TTC in assessing pesticide metabolites (member of PPR WG) and in its lower tier use on risk assessment of mixtures (WHO/IPCS). The outcome of this task is a report (D 2.3, M24) describing the use of the TTC approach to prioritise chemicals for mixture testing.

Report describing cumulative assessment groups for a broad range of chemicals, based on information extracted from (literature) databases

This task will be performed by RIKILT, BPI, SGL, UMIL and KI provide a list of chemicals that serve as a basis for the other tasks in this WP (Milestone 2.1, M4). This list will not only contain pesticides that are classified in cumulative assessment groups as recently established by EFSA’s PPR panel. EuroMix partners UMIL, ANSES and RIVM have provided EFSA with an approach for grouping pesticides and the basic toxicological data required for this. In this task, a similar strategy will be set up and used for the grouping of non-pesticide chemicals. The following chemical classes will be considered: Environmental pollutants (e.g. dioxins, PAHs), food contaminants (e.g. mycotoxins), chemical migrants from food package materials (NIAS), known and suspected endocrine active chemicals, biocides, and bioactive alkaloids (e.g. pyrrolizidine alkaloids). To that end, publicly available data sources and (literature) databases, such as e-ChemPortal, GEMS/Food Program, and EFSA databases, will be exploited. The final list of this task will consist of chemicals with known and suspected toxicity with focus on the endpoints selected for the EuroMix project, i.e. liver toxicity, developmental toxicity, endocrine effects and immunotoxicity. The literature review and database searches will result in in a report (Deliverable 2.1, M18).

Scientific article describing the PB-PK model for combined exposures

INERIS will develop specific metabolic pathways models for the substances to be studied and will couple them to the PB-PK model of URV. INRA will perform dedicated in-vitro experiments with primary hepatocytes to obtain values for metabolic rate constants (Vmax, Km, etc.) for the substances studied. Other parameter values will be obtained from the literature or QSAR modelling. For mechanistic (systems biology) PD modelling on the basis of specific MoAs for endocrine descriptors and hepatotoxicity, the two models recently published by INERIS on steroidogenesis and nrf2/GSH pathway will be adapted and coupled to the PB-PK + metabolism model just described. The PB-PK-PD models developed will be first aimed to guide in-vivo experiments on selected endpoints and groups of compounds. They will also be used for IVIVE, prediction of cumulative exposures (WP3), potential biomarkers levels in humans (WP7) and will be made available to the toolbox of WP6. (M24). The PB-PK/D modelling exercise and results will be described in deliverable 4.2.

Report on stakeholder workshop 1

The project will only be truly successful if its outcomes are widely used by relevant stakeholders, and survive beyond the end of the project. Therefore, it is important that the project will deliver results that meet the needs of the stakeholders, and that stakeholders are aware of it. This necessitates continued stakeholder involvement throughout the project. To accomplish this a number of stakeholder activities are planned: •Freshfel will organise 1-2 small-specialised workshops and face-to-face meetings with representative of the food sector and GLOBAL G.A.P; •WHO will organise a workshop to discuss food coding and modelling issues for countries outside Europe; •Midway through the project, an international workshop will be organised to inform stakeholders of progress, and obtain their feedback regarding their needs and consultation regarding the work undertaken as well as which further steps can be taken to ensure project relevance for them and the way forward.

Minutes of meetings discussing harmonisation between Europe, EPA and WHO

The EuroMix has defined liver, endocrine and developmental immuno toxicological endpoints as test cases and consequently experiments will be performed throughout the whole project addressing these endpoints. Horizontal activity leaders (KI, ICL) will collect information from other WPs and will summarize the findings in line with OECD discussions and test regulation. They will pursued the new guidance developed in task 8.2 on how new mechanism-based testing should be addressed in existing OECD, EFSA, ECHA and/or ECVAM guidelines or proposals to adapt this existing test guidance. DG SANCO has started an e-working group to discuss and to implement cumulative risk assessment. Probabilistic modelling as recommended in the EFSA guidance has been implemented in the ACROPOLIS IT tool. The EuroMix project will continue to build upon this tool (see WP6). DTU will summarize the discussions and achievements of DG SANCO’s e-working group and will fine-tune the findings with work to be done in WP5. Furthermore, they will forward useful result of EuroMix exposure assessment to the SCFCAH. Deliverable 9.2 (M45).

Scientific paper ready for submission on models and software for QIVIVE and AOP

A functional design will be prepared by INERIS, in collaboration with URV, RIVM, DLO-R and DLO-B, with advice from EPA and ICL (Milestone 6.3, M24). Models to calculate benchmark doses (or similar hazard characterisation measures) for chemicals and/or mixtures of chemicals from omics and/or bioassay data obtained from in-vitro studies (from WP 4), calibrated on similar measurements in animal studies. A method to select predictive gene or metabolite sets will be implemented. The design will be based on the experiments and models in WP3 and WP4, and on the experience of INERIS and URV and others (e.g. systems biology and PB-PK models for evaluating metabolic interactions in complex mixtures. The AOP module will contain simplified models for general use, and advanced models for perturbation by triazoles of steroidogenesis and the nrf2/GSH system. The system biological models will be integrated with PB-PK models developed in WP4. The design will include a module for dose-response modelling (RIVM, DLO-B, EPA) including benchmark approaches such as PROAST and BMDS. DLO-B and EPA will work on an optimal connection between the EuroMix web-based models and the ToxCast database. The functional design will describe input-output relations needed to link the EuroMix web-based model toolbox to existing or newly developed modules. The new functionality and a case study will be reported in a draft scientific paper (D6.3, M48).

Report on the use of in-silico methods for the prioritisation of mixtures thereof

In this Task DEFRA, RIVM and UMIL will explore the use of in-silico approaches for the identification/prioritisation of compounds and mixtures in relation to assessment of effects associated with the selected endpoints. In-silico methods will include (Q)SARs, toxicity expert systems, and read-across approaches. DEFRA scientists participating in this task have longstanding expertise in data mining and in-silico modelling. RIVM is project management group member OECD QSAR ToolBox and advisory board member for the Danish (Q)SAR Database. Furthermore, UMIL has expertise with in-silico tools/computational models particularly for Endocrine Active Substances. Using the list of compounds identified in Task 2.1, chemical categories and sub-categories will be defined on the basis of physicochemical, structural and mechanistic similarities.For this, the task will use the in silico profilers and extensive databases available within the OECD QSAR ToolBox, as well as the additional 25 high quality toxicity datasets assembled and added to the ToolBox by DEFRA, the DEREK expert system (Lhasa ltd.) and chemometric tools such as ChemoTyper. Chemical categories will be further divided into sub-categories of compounds that have similar or dissimilar mechanistic modes of action. This will enable choosing different combinations of the chemicals within and between (sub)categories. The selected compounds and mixtures thereof will then be tested in a hypotheses driven manner through experiments performed in WP3 and WP4, i.e. to verify the in-silico predictions, and use the experimental values to adjust the models where appropriate. A critical milestone within this task concerns a list of compounds and mixtures for further testing using in vitro and ‘omics’ based methods in WP3 and WP4 (Milestone 2.2, M12). A report will be written on the use of in-silico methods for the prioritisation of substances in the context of mixtures testing (Deliverable 2.2, M18)

Scientific article ready for submission describing the in vitro testing strategy for immune toxicity

The most pertinent in vitro tests as selected in task 3.1 will be used to test a broader range of chemicals selected within WP2 and WP5. . Mixtures of chemicals that are listed in CAG as established by the PPR panel of EFSA for pesticides will be chosen, as well as mixtures of pesticides and non-pesticides, and these will be tested with the battery of in vitro assays as well as with the CAG-specific PCR arrays. The dose-response effects of the individual chemicals (similar and dissimilar MoA) will be compared to those of the mixtures in order to determine whether the mixtures are behaving according to the CA or IA model (WP4). The outcome of the tests will be used for the selection of a limited number of index compounds to be tested as single chemicals and as mixtures in an in-vivo study for the validation of the in-vitro results (WP4.3; M3.2). The results of Task 3.3 will be compared with the outcome of the animal studies conducted within WP4. The results for immuun toxicity will be described in a scientific articles ready for submission (Deliverable 3.4) which will be ready in M42.

Report on the needs and attitudes of stakeholders to the test strategy

The project will identify and interview international consumer groups, non-governmental organizations, retailers, regulators, quality managers of multiples food suppliers and consumers regarding their needs and resources in terms of performing risk assessment. Besides assessing potential opportunities, threats, strength and weaknesses from the stakeholders’ perspective, the level of understanding and acceptability of different developed concepts and perceived information needs will also be explored. The current task includes drafting of the study protocol and interview guides, execution and transcription of the interviews. To identify and select appropriate stakeholders, UGent will rely on FOOD2Know, a food research platform with multiple stakeholders and various ongoing international partnerships with stakeholders in food safety around the world in particular. The results will be reported in draft scientific publications ready for submission as deliverable 8.1. (M24).

The use of QSAR and TTC approaches to prioritise chemicals for mixtures

The predictive value of individual QSAR models has been discussed in several publications. It has been shown repeatedly that appropriate combined use of QSAR models in an Integrated Testing Strategy, or in a statistical (Bayesian) Weight of Evidence procedure allows the user to select substances for which the prediction of toxicity has sufficiently high reliability. On the basis of the experiences obtained in the preceding tasks, Fera and RIVM, with support of all other WP1 partners, will set up a strategy for the integrated use of QSAR and TTC approaches in the testing of mixtures. The outcome of this task will be a detailed report (Deliverable 2.4, M36) that will be used to provide guidance on when and how to go to higher tiers in the tiered testing strategy formulated in WP8.

Specific recommendations regarding implementation of a mechanism-based test strategy for liver, developmental and endocrine for OECD

The EuroMix has defined liver, endocrine and developmental immuno toxicological endpoints as test cases and consequently experiments will be performed throughout the whole project addressing these endpoints. Horizontal activity leaders (KI, ICL) will collect information from other WPs and will summarize the findings in line with OECD discussions and test regulation. They will pursued the new guidance developed in task 8.2 on how new mechanism-based testing should be addressed in existing OECD, EFSA, ECHA and/or ECVAM guidelines or proposals to adapt this existing test guidance. DG SANCO has started an e-working group to discuss and to implement cumulative risk assessment. Probabilistic modelling as recommended in the EFSA guidance has been implemented in the ACROPOLIS IT tool. The EuroMix project will continue to build upon this tool (see WP6). DTU will summarize the discussions and achievements of DG SANCO’s e-working group and will fine-tune the findings with work to be done in WP5. Furthermore, they will forward useful result of EuroMix exposure assessment to the SCFCAH. Deliverable 9.2 (M45).

Report of WHO consultation workshop and feasibility study

WHO, with help of RIVM, in its capacity of WHO/FAO collaborating centre for food safety, and Ugent, having global experience based on the EU funded project Veg-i-trade, will define achievable goals for higher tier assessment at the global level. Data at WHO is structured differently from EFSA and different from the USA. WHO and EFSA have made a conversion table for GEMS FOOD and FoodEx and the usability of this table will be tested and when possible implemented in WP6. WHO, Ugent and RIVM will define a will provide instructions how exposure assessment as performed in WP5 can be reproduced in Brazil and Thailand. Brazil and Thailand have been added to the project as associated partners. A report with recommendations on the achievability of aggregated exposure assessment outside EU will be produced after a WHO consultation of about 15 non-EU experts during 3 days. . Brazil and Thailand would have been in charge of preparing the background documents and example. Such a report would be more official than a simple study report and would have relatively limited additional costs (about 50 K€ for travels and per diem). The WHO will report the reproducibilty and feasibility of exposure assessment outside Europe in deliverable 9.4.

Scientific article ready for submission describing the results of the in vitro testing of mixtures

The most pertinent in vitro tests as selected in task 3.1 will be used to test a broader range of chemicals selected within WP2 and WP5. Mixtures of chemicals that are listed in CAG as established by the PPR panel of EFSA for pesticides will be chosen, as well as mixtures of pesticides and non-pesticides, and these will be tested with the battery of in vitro assays as well as with the CAG-specific PCR arrays. The dose-response effects of the individual chemicals (similar and dissimilar MoA) will be compared to those of the mixtures in order to determine whether the mixtures are behaving according to the CA or IA model (WP4). The outcome of the tests will be used for the selection of a limited number of index compounds to be tested as single chemicals and as mixtures in an in-vivo study for the validation of the in-vitro results (WP4.3; M3.2). The results of Task 3.3 will be compared with the outcome of the animal studies conducted within WP4. The results will be described in a scientific articles (Deliverable 3.5) which will be ready in M42.

Plan for the dissemination and exploitation of the results from EuroMix

The Plan defines a clear set of actions for the 4 years including purpose, target group, method, vehicle, timing and success criteria. •Definition of target audiences: Foreseeable target groups include risk managers & decision makers from EC and members state authorities, risk assessors at European and international state authorities, scientific community, industry-led stakeholder forums (as ETPs), NGOs, health, agricultural and environmental sectors as well as the food and beverage industry and others identified during the project. •Selection of key messages for each target audience. •Planning and tailored communication channels for each target audience (e.g. press releases, workshops, conferences, scientific publications, newsletters, mail based lists, websites, social networks, etc.). •Regular revision and update of the Plan for the dissemination and exploitation of project´s results to give a cumulative overview of the activities undertaken and planned in EuroMix. The final version will provide a long-term strategy for post-project activities. Role of participants: MATIS will coordinate this task and be responsible for the regular revision of the Plan for the dissemination and exploitation of project´s results. WP10 partners and HA leaders will contribute to planning and tailoring communication channels for each target audience. All other partners of the consortium will have input into the identification of additional target groups.

Report on the comparative outcome of using new mechanism-based testing and consequences for animal testing and uncertainties in risk assessment

KI will make a proposal of the relevant elements to integrate in a tiered assessment strategy (milestone 8.3). The web-based EuroMix tool developed in WP6 will be used for test runs of case studies (identified in WP2-WP4) to test the proposed criteria. The extensive toxicological testing from a wide range of techniques and experimental models, including e.g. in-silico, in-vitro, in-vivo, and PB-PK/D experiments, conducted by EuroMix will provide an excellent basis to evaluate the outcome of proposed approach as compared with current methods/models for risk assessment, and the pro’s and con’s of different approaches will be discussed. The results will be described in deliverable 8.5 (M45) and will be used in WP9 and WP10. KI, in cooperation with INRIS, RIVM, UMIL, DLO-B and DEFRA will elaborate on the consequences for animal testing once the mechanism-based test strategy has been developed. The use of PB-PK modelling, IVIVE and system toxicology should reduce the uncertainties in current risk assessment approaches, and the new uncertainty components of the EuroMix tool (Task 6.5) will be used to evaluate this. KI will write a discussion document for exchanging views with stakeholders, including 3R-focused organisations. Input is required from several work packages (see task 3.4 and 4.4) and The results will be used in WP9 and WP10 for guidance, training and implementation (deliverable D8.5; M45)

Gender Plan

RIVM is responsible for the implementation of a gender management strategy and promote gender equality.

Scientific paper ready for submission on the EuroMix toolbox and software

DLO-B, together with ICL, ANSES, DEFRA, URV and others, will optimize and implement models for compound prioritization based on Margin of Exposure (MoE) in a ‘refine and retain’ setting. This will provide a practical implementation of the RISK21 matrix approach in a fully probabilistic setting. The QALIBRA model will be linked into the EuroMix tool, in collaboration between DLO-B and DEFRA. A functional design for the general design and the uncertainty aspects of the EuroMix tool (Milestone 6.4, M24) will be prepared by DLO-B and DEFRA. DLO-B will propose a general software design for an integrated web-based model composed of modules for dietary exposure, non-dietary exposure, in-vitro and in-vivo hazard characterizations using a bioassay and omics toolbox, and models to link the different parts (based on PB-PK, systems biology, benchmark dose modelling and probabilistic margin of exposure). The software will include simpler models in a tiered approach as well. DLO-B will design the front-end for different user categories. DEFRA will propose a comprehensive general approach for addressing uncertainty in aggregate exposure and risk assessments, building on the recommendations of the EFSA working group on uncertainty. Both qualitative and quantitative approaches will be considered. The uncertainty in the exposure will be quantified and uncertainties related to exposure assessment and risk characterisation will be identified. Sensitivity analyses will be also applied to determine key parameters within the EuroMix tool used in the tiered approach to CAG creation and assessment, as part of WP8. The final EuroMix model toolbox will be described in a draft scientific paper (D6.4, M48).

Scientific paper ready for submission describing the PB-PK/D model approach

Biological materials (serum samples and/or leucocytes) from subjects with known exposure to the selected chemicals in the mixture (task 7.2) will be analysed for biomarkers of effects as selected based on the studies in WP3 and WP4 focussing on hepatic, developmental or endocrine endpoints. The exact identification of the biomarkers of effects need to await reporting of the results from the in vivo and in vitro study but might include clinical chemistry endpoints, RNA array profiling data, DNA and/or protein adducts or other biochemical markers associated with the effects observed. Based on the biomarkers selected appropriate laboratories performing these analyses will be selected based on experiences and methods available. Inter-individual variability in the biomarkers of effect will be studied. The PB-PK models and Adverse Outcomes Pathways developed in Acropolis and further refined in WP3 – WP6 will be used to model the effects of exposures to the chemicals in the mixture as selected in WP2. Human variability in such biomarkers will be estimated by population Monte-Carlo simulations. The results will be described in a scientific paper (deliverable 7.3 (M45))

Scientific article rady for submission on cumulative assessment of mixtures of several chemical classes

ANSES, in cooperation with RIVM, will define exposure scenarios. The scenarios will address the cumulative assessment groups defined by EFSA and based on data organized in task 5.1. ANSES, RIVM, CZU, MATIS, Ugent, HSE, NIJZ, URV, BPI and Ministry of Health of the Republic Cyprus will divide the exposure scenarios and chemicals of interest. Exposure calculations will be performed using probabilistic methods already implemented in the ACROPOLIS-IT tool, which is part of the EuroMix web-based model toolbox. Depending on the nature of the risk (acute or chronic), exposure will be estimated at the person-day or person level, respectively. Acute exposure will be calculated by Monte Carlo integration of consumption and concentration distributions. Chronic exposure will be calculated using the Logistic Normal-Normal (LNN) model. NIJZ, BPI and Ministry of Health of the Republic Cyprus will search for processing factors in the open literature and/or Draft Assessment Reports. The calculations will account for processing effects and unit variability as far as practically possible. This will result in a scientific article ready for submission on cumulative assessment of mixtures of several chemical classes (deliverable 5.3).

Scientific article ready for publication balancing risk of mixtures against benefits

Positive health effects of food will be evaluated by using the Qalibra tool. The BRAFO test strategy for risk-benefit analyses will be applied for balancing the risk of mixtures against beneficial components in the same food. MATIS, UGent, URV and DEFRA will address this issue in a case study to be selected one year into the project. The selected case study will be one of the following: 1) the benefit of consuming fruits and vegetables vs. the combined risk of pesticides present in the same food stuffs on the effects of concern studied in WP3 and 4. The case study will be reported in a draft scientific paper as deliverable 8.2 (M36).

Position paper on gaps to be filled in existing legislation

BfR and BPI will prepare an overview of how mixture testing and higher tier modelling are addressed in current regulatory toxicology and how it should be addressed ideally in the future. This will be complementary to task 8.2. The focus will be on general aspects related to EFSA and DG SANCO discussion, the need to reduce animal testing and to specific aspects related to the chemicals selected in the EuroMix. BfR, BPI and ICL will identify potential gaps in legislation and will provide recommendations on how the EuroMix test approaches and assessment strategies including non-testing approaches should be placed in the context of OECD, EFSA, ECHA and ECVAM guidelines or guidance documents. They will produce a position paper (Deliverable 9.1) that can be discussed with the DG SANCO, DG ENV, EFSA and ECHA and can be used in the stakeholder conference (see WP10). D9.1 will be ready in M18. The discussion paper will overview current on-going discussion and the need for quality control in general terms. This will be done in close cooperation with the Joint Research Centre.

Scientific article ready for submission describing the in vitro testing strategy for developmental/endocrine toxicity

The most pertinent in vitro tests as selected in task 3.1 will be used to test a broader range of chemicals selected within WP2 and WP5. . Mixtures of chemicals that are listed in CAG as established by the PPR panel of EFSA for pesticides will be chosen, as well as mixtures of pesticides and non-pesticides, and these will be tested with the battery of in vitro assays as well as with the CAG-specific PCR arrays. The dose-response effects of the individual chemicals (similar and dissimilar MoA) will be compared to those of the mixtures in order to determine whether the mixtures are behaving according to the CA or IA model (WP4). The outcome of the tests will be used for the selection of a limited number of index compounds to be tested as single chemicals and as mixtures in an in-vivo study for the validation of the in-vitro results (WP4.3; M3.2). The results of Task 3.3 will be compared with the outcome of the animal studies conducted within WP4. The results for endocrine/developmental will be described in a scientific articles ready for submission (Deliverable 3.3) which will be ready in M42.

Scientific article ready for submission describing the in vitro testing strategy for liver toxicity

The most pertinent in vitro tests as selected in task 3.1 will be used to test a broader range of chemicals selected within WP2 and WP5. . Mixtures of chemicals that are listed in CAG as established by the PPR panel of EFSA for pesticides will be chosen, as well as mixtures of pesticides and non-pesticides, and these will be tested with the battery of in vitro assays as well as with the CAG-specific PCR arrays. The dose-response effects of the individual chemicals (similar and dissimilar MoA) will be compared to those of the mixtures in order to determine whether the mixtures are behaving according to the CA or IA model (WP4). The outcome of the tests will be used for the selection of a limited number of index compounds to be tested as single chemicals and as mixtures in an in-vivo study for the validation of the in-vitro results (WP4.3; M3.2). The results of Task 3.3 will be compared with the outcome of the animal studies conducted within WP4. The results for liver toxicty wiill be described in scientific article ready for submission (Deliverable 3.2) which will be ready in M42.

Demonstration tool cumulative exposure assessment

ANSES, in cooperation with RIVM, will define exposure scenarios. The scenarios will address the cumulative assessment groups defined by EFSA and based on data organized in task 5.1. ANSES, RIVM, CZU, MATIS, Ugent, HSE, NIJZ, URV, BPI and Ministry of Health of the Republic Cyprus will divide the exposure scenarios and chemicals of interest. Exposure calculations will be performed using probabilistic methods already implemented in the ACROPOLIS-IT tool, which is part of the EuroMix web-based model toolbox. Depending on the nature of the risk (acute or chronic), exposure will be estimated at the person-day or person level, respectively. Acute exposure will be calculated by Monte Carlo integration of consumption and concentration distributions. Chronic exposure will be calculated using the Logistic Normal-Normal (LNN) model. NIJZ, BPI and Ministry of Health of the Republic Cyprus will search for processing factors in the open literature and/or Draft Assessment Reports. The calculations will account for processing effects and unit variability as far as practically possible. This will result a demonstration tool (deliverable 5.2).

Demonstration prototype of EuroMix model toolbox (module priority setting).

In an early stage, ANSES will provide a method for identification of major mixtures in terms of exposure, based on the model developed in the PERICLES programme (Béchaux et al. 2013). DLO-B with the help of ANSES will implement a module to select the appropriate combinations of chemicals for mixture experiments of combined exposure to multiple food-related toxic substances, based on exposure patterns, possibly weighted by relative potency factors (Milestone 6.1, M6). The chemicals contributing most to the exposure will be identified, and will be the basis for mixture testing in WP3 and WP4. These models will be tested using data gathered in Task 5.1 (M7-9). DLO-B will provide a demonstration prototype of the EuroMix model toolbox to integrate exposure assessment of selected and unselected chemicals based on a ‘Retain and refine’ concept (Deliverable 6.1, M18).

Proceedings and training material from second training session for stakeholders

To maximise implementation of the new risk assessment strategies developed in the project, training will be given for the stakeholders who will use the new integrated models. The aim of the training sessions is that the stakeholders will gain understanding of the scientific basis behind the new risk assessment strategies, be able to use the developed tools and to interpret and assess the output as well as implement the strategies in their own context. The training will be developed with input from the Scientific Advisory Board and from user groups from industry and authorities, which will test the tools. •Two training sessions will be organised for stakeholders from industry, risk assessors for national and European authorities and for risk managers from European Commission and members state authorities • Training material that will be developed will also be available for online learning to allow for a wide uptake Role of participants: KI will coordinate the development of the training sessions and the other partners will contribute to the development of the training, prepare training material and be trainers. KI will write proceedings and training materials from from the second session (del 10.6).

Proceedings and training material from first training session for stakeholders

To maximise implementation of the new risk assessment strategies developed in the project, training will be given for the stakeholders who will use the new integrated models. The aim of the training sessions is that the stakeholders will gain understanding of the scientific basis behind the new risk assessment strategies, be able to use the developed tools and to interpret and assess the output as well as implement the strategies in their own context. The training will be developed with input from the Scientific Advisory Board and from user groups from industry and authorities, which will test the tools. •Two training sessions will be organised for stakeholders from industry, risk assessors for national and European authorities and for risk managers from European Commission and members state authorities •Training material that will be developed will also be available for online learning to allow for a wide uptake. Role of participants: KI will coordinate the development of the training sessions and the other partners will contribute to the development of the training, prepare training material and be trainers.KI will write proceedings and training materials from the first training session for stakeholders (del 10.4).

Final version of EuroMix model toolbox including hazard and PB-PK/D models

This task will implement in the probabilistic setting of the EuroMix tool a) PB-PK models to convert external exposure to organ-level exposure; b) extrapolation methods from in-vitro to in-vivo exposure (QIVIVE module). Based on simulations INERIS will provide a functional design, in collaboration with URV, RIVM and DLO-B (Milestone 6.3, M18). There will be models for both data-rich and data-poor situations, so that calculations can be done for large numbers of chemicals. After discussion on the consortium level, including a comparison with high-throughput QIVIVE methods of EPA, selected models will be made suitable for linking in an R implementation by INERIS, URV and/or RIVM, or directly implemented in the EuroMix tool by DLO-B, with the help of INERIS, URV, RIVM and/or others. Final version of EuroMix model toolbox including hazard and PB-PK/D models will be delivered by DLO as deliverable 6.2 in M42.

CAG-specific PCR arrays

Transcriptomic analysis will be conducted in order to obtain information on the level of gene regulation in the different cellular models. Rat/human primary hepatocytes (INRA) and HepaRG cells/HepG2 cells (liver; BfR, INRA, RIKILT), MCF7 breast cells (endocrine effects; RIKILT), zebrafish embryos/stem cells (development; RIVM/KI) and JURKAT cells (immunotox; RIKILT) will be treated with the training compounds, total RNA will be extracted from the cells and subjected to hybridisation with whole genome arrays. The array data of all partners will be imported into a central database managed by DLO-B and (upon publication of the data) submitted to the ArrayExpress Database of EMBL-EBI (see also WP6 Task 6.3). Bioinformatics will be employed by using software tools to generate molecular networks based on the microarray data yielding molecular signalling, toxicity and/or metabolic pathways being deregulated (e. g. Ingenuity Pathway Analysis, BfR; RIKILT). Within this analysis, we will also refer to a number of databases of expression profiles of toxicants that are currently becoming available. These are, e.g., the “Connectivity Map”, which is a resource of 6100 arrays with expression profiles of more than 1300 compounds mainly used for exposure of MCF7 cells and which has recently been expanded and is now containing data of more than 5500 perturbations and 18 cell lines (http://lincscloud.org/). Other relevant databases considered are “Drugmatrix” (https://ntp.niehs.nih.gov/drugmatrix/index.html), “Dixa” (http://wwwdev.ebi.ac.uk/fg/dixa/index.html), and “TG Gates” (http://toxico.nibio.go.jp/open-tggates/english/search.html. Specific target areas of the embryo (UMIL) will be examined for specific gene expression related to retinoic acid metabolism, that is involved in malformations. Based on the bio-informatic analysis, similar and dissimilar MoA will be defined among the tested compounds crucial for grouping these compounds into CAGs. The results of the transcriptomic analysis will also be used for model building within WP6 (Task 6.4). The molecular signatures obtained by the transcriptomic approach, as well as the information generated by the models developed in WP6, will be used for the selection of sets of commonly modulated genes in order to develop CAG-specific PCR arrays as a deliverable (D3.1, M24), that will subsequently be used for testing and grouping of additional chemicals and for mixtures (see below).

PB-PK/D modelling for the index compound of the chosen endpoints

INERIS, URV and INRA will take the lead in PB-PK/D modelling for both single chemicals and combined exposures. The generic PB-PK/D model already developed at URV will be extended to include inhalation and dermal exposure components. The PB-PK/D models for the index compounds will be described in deliverable 4.1.

Pan for managing and releasing open data

The coordinator will made a plan for the management of open data before month 6 and will discuss the plan during the second consortium meeting. The plan, deliverable 1.2, will be submitted to DG Research according to the new requirements in Horizon2020 in month 6.

Publications

Review on crosstalk and common mechanisms of endocrine disruptors: Scaffolding to improve PBPK/PD model of EDC mixture

Author(s): Raju Prasad Sharma, Marta Schuhmacher, Vikas Kumar
Published in: Environment International, Issue 99, 2017, Page(s) 1-14, ISSN 0160-4120
DOI: 10.1016/j.envint.2016.09.016

Developing integrated PBPK/PD coupled mechanistic pathway model (miRNA-BDNF): An approach towards system toxicology

Author(s): Raju Prasad Sharma, Marta Schuhmacher, Vikas Kumar
Published in: Toxicology Letters, Issue 280, 2017, Page(s) 79-91, ISSN 0378-4274
DOI: 10.1016/j.toxlet.2017.08.003

Case study: Exposure to mixtures of chemicals in a human study and verification of aggregated exposure models with real-life data

Author(s): H. Dirven, M. Andreassen, C. Karrer, N. von Goetz, A.K. Sakhi, T. Husøy
Published in: Toxicology Letters, Issue 295, 2018, Page(s) S2, ISSN 0378-4274
DOI: 10.1016/j.toxlet.2018.06.011

High-Throughput Analysis of Ovarian Cycle Disruption by Mixtures of Aromatase Inhibitors

Author(s): Frederic Y. Bois, Nazanin Golbamaki-Bakhtyari, Simona Kovarich, Cleo Tebby, Henry A. Gabb, Emmanuel Lemazurier
Published in: Environmental Health Perspectives, Issue 125/7, 2017, Page(s) 077012, ISSN 0091-6765
DOI: 10.1289/ehp742

Development and validation of PBPK model for DEHP and its metabolites: Application to cohort and case–control studies

Author(s): Raju Prasad Sharma, Marta Schuhmacher, Vikas Kumar
Published in: Toxicology Letters, Issue 280, 2017, Page(s) S284, ISSN 0378-4274
DOI: 10.1016/j.toxlet.2017.07.796

The development of a pregnancy PBPK Model for Bisphenol A and its evaluation with the available biomonitoring data

Author(s): Raju Prasad Sharma, Marta Schuhmacher, Vikas Kumar
Published in: Science of The Total Environment, Issue 624, 2018, Page(s) 55-68, ISSN 0048-9697
DOI: 10.1016/j.scitotenv.2017.12.023

Head skeleton malformations in zebrafish (Danio rerio) to assess adverse effects of mixtures of compounds

Author(s): Yvonne C. M. Staal, Jeroen Meijer, Remco J. C. van der Kris, Annamaria C. de Bruijn, Anke Y. Boersma, Eric R. Gremmer, Edwin P. Zwart, Piet K. Beekhof, Wout Slob, Leo T. M. van der Ven
Published in: Archives of Toxicology, Issue 92/12, 2018, Page(s) 3549-3564, ISSN 0340-5761
DOI: 10.1007/s00204-018-2320-y

Physiologically Based Pharmacokinetic (PBPK) Modeling of the Bisphenols BPA, BPS, BPF, and BPAF with New Experimental Metabolic Parameters: Comparing the Pharmacokinetic Behavior of BPA with Its Substitutes

Author(s): Cecile Karrer, Thomas Roiss, Natalie von Goetz, Darja Gramec Skledar, Lucija Peterlin Mašič, Konrad Hungerbühler
Published in: Environmental Health Perspectives, Issue 126/7, 2018, Page(s) 077002, ISSN 0091-6765
DOI: 10.1289/ehp2739

Modelling aggregate exposure to pesticides from dietary and crop spray sources in UK residents

Author(s): Marc C. Kennedy, David G. Garthwaite, Waldo J. de Boer, Johannes W. Kruisselbrink
Published in: Environmental Science and Pollution Research, Issue 26/10, 2019, Page(s) 9892-9907, ISSN 0944-1344
DOI: 10.1007/s11356-019-04440-7

Development of a human physiologically based pharmacokinetic (PBPK) model for phthalate (DEHP) and its metabolites: A bottom up modeling approach

Author(s): Raju Prasad Sharma, Marta Schuhmacher, Vikas Kumar
Published in: Toxicology Letters, Issue 296, 2018, Page(s) 152-162, ISSN 0378-4274
DOI: 10.1016/j.toxlet.2018.06.1217

Relative potency ranking of azoles altering craniofacial morphogenesis in rats: An in vitro data modelling approach

Author(s): Francesca Di Renzo, Francesca Metruccio, Maria Battistoni, Angelo Moretto, Elena Menegola
Published in: Food and Chemical Toxicology, Issue 123, 2019, Page(s) 553-560, ISSN 0278-6915
DOI: 10.1016/j.fct.2018.12.004

Overview on legislation and scientific approaches for risk assessment of combined exposure to multiple chemicals: the potential EuroMix contribution

Author(s): S. Rotter, A. Beronius, A. R. Boobis, A. Hanberg, J. van Klaveren, M. Luijten, K. Machera, D. Nikolopoulou, H. van der Voet, J. Zilliacus, R. Solecki
Published in: Critical Reviews in Toxicology, Issue 48/9, 2018, Page(s) 796-814, ISSN 1040-8444
DOI: 10.1080/10408444.2018.1541964

Adverse Outcome Pathway-Driven Analysis of Liver Steatosis in Vitro : A Case Study with Cyproconazole

Author(s): Claudia Luckert, Albert Braeuning, Georges de Sousa, Sigrid Durinck, Efrosini S. Katsanou, Parthena Konstantinidou, Kyriaki Machera, Emanuela S. Milani, Ad A. C. M. Peijnenburg, Roger Rahmani, Andreja Rajkovic, Deborah Rijkers, Anastasia Spyropoulou, Marianna Stamou, Geert Stoopen, Shana Sturla, Bernd Wollscheid, Nathalie Zucchini-Pascal, Alfonso Lampen
Published in: Chemical Research in Toxicology, Issue 31/8, 2018, Page(s) 784-798, ISSN 0893-228X
DOI: 10.1021/acs.chemrestox.8b00112

Selecting mixtures on the basis of dietary exposure and hazard data: application to pesticide exposure in the European population in relation to steatosis

Author(s): Amélie Crépet, Marie Vanacker, Corinne Sprong, Waldo de Boer, Urska Blaznik, Marc Kennedy, Chris Anagnostopoulos, Despo Louca Christodoulou, Jiří Ruprich, Irena Rehurkova, José Luis Domingo, Bodil Hamborg Jensen, Francesca Metruccio, Angelo Moretto, Liesbeth Jacxsens, Pieter Spanoghe, David Senaeve, Hilko van der Voet, Jacob van Klaveren
Published in: International Journal of Hygiene and Environmental Health, Issue 222/2, 2019, Page(s) 291-306, ISSN 1438-4639
DOI: 10.1016/j.ijheh.2018.12.002

Quantitative AOP based teratogenicity prediction for mixtures of azole fungicides

Author(s): Maria Battistoni, Francesca Di Renzo, Elena Menegola, Frederic Yves Bois
Published in: Computational Toxicology, Issue 11, 2019, Page(s) 72-81, ISSN 2468-1113
DOI: 10.1016/j.comtox.2019.03.004

Assessment of reproductive toxicity of male rats through maternal exposure to dienestrol

Author(s): N. González, E. Schreiber, M. Torrente, V. Kumar, J.L. Domingo, M.M. Gómez
Published in: Toxicology Letters, Issue 295, 2018, Page(s) S133, ISSN 0378-4274
DOI: 10.1016/j.toxlet.2018.06.701

Finding synergies for 3Rs – Toxicokinetics and read-across: Report from an EPAA partners' Forum

Author(s): Charles Laroche, Manoj Aggarwal, Hans Bender, Paul Benndorf, Barbara Birk, Jonathan Crozier, Gianni Dal Negro, Federica De Gaetano, Christian Desaintes, Iain Gardner, Bruno Hubesch, Amaia Irizar, David John, Vikas Kumar, Alfonso Lostia, Irene Manou, Mario Monshouwer, Boris P. Müller, Alicia Paini, Kirsty Reid, Timothy Rowan, Magdalini Sachana, Katrin Schutte, Catrina Stirling, Rob Taalman, Leon v
Published in: Regulatory Toxicology and Pharmacology, Issue 99, 2018, Page(s) 5-21, ISSN 0273-2300
DOI: 10.1016/j.yrtph.2018.08.006

Cellular and molecular correlates of cyproconazole-induced steatosis and inflammation in an in vitro model of human liver cells

Author(s): Pascale Folini
Published in: Master’s Thesis ETH Zurich, Department D-HEST, 2016, Page(s) 1-98

Chemical-induced steatosis in an in vitro human liver cell model

Author(s): Klara Hauser
Published in: Bachelor’s Thesis ETH Zurich, Department D-HEST, 2016, Page(s) 1-36

Physiologically based pharmacokinetic modelling of Bisphenol A in humans

Author(s): Nicole Cramer
Published in: 2016

Exposure assessments of bisphenol S and F

Author(s): Yaping Cai
Published in: 2016

PBPK Modelling of BPA & BPF

Author(s): Thomas Roiss
Published in: 2016

Aggregate and cumulative exposure assessment of the endocrine disrupting chemicals 4-nonylphenol and bis(2-ethylhexyl)-phthalate

Author(s): Patrick Fitzgerald
Published in: 2017

Review on Cumulative Risk Assessments of Endocrine Disrupting Chemicals

Author(s): Zhehui Chen
Published in: 2018

Consumer Exposure to Bisphenolic Compounds: Advancing Exposure and Pharmacokinetic Modeling

Author(s): Karrer, Cecile
Published in: 2019
DOI: 10.3929/ethz-b-000336637

A method to evaluate skeletal malformations in zebrafish embryos (in view of mixture toxicity assessment)

Author(s): Jeroen Meijer
Published in: 2016

Skeletal malformations in zebrafish embryos to assess mixture effects

Author(s): Remco van der Kris
Published in: 2016

The effect of mixtures on the development of the zebrafish

Author(s): Anke Boersma
Published in: 2016

Analysis of Head Skeletal Malformation in Zebrafish Embryos for Chemical Mixture Assessment: phenotype and Mode of Action

Author(s): Ananditya Nugraha
Published in: 2017

Effects of chemical mixtures on the development of the head skeleton of zebrafish embryos and on sexual development of the zebrafish

Author(s): Sharon Compeer
Published in: 2017

Mode of action definition in the context of mixture effects on skeletal development in zebrafish embryos

Author(s): Jan-Jaap Sirks
Published in: 2018

Analysis of the Mode of Action of chemicals inducing head skeletal malformations in zebrafish embryos

Author(s): Vivianne Veenma
Published in: 2018

Gene expression patterns in zebrafish as an endpoint for the development of craniofacial aberrations caused by (environmental) pollutants

Author(s): Carina Sujan
Published in: 2019

Application of the dose addition model in complex mixture risk assessment

Author(s): Paul van Ommeren
Published in: 2019

S01.04.07. Verification of Aggregated Exposure to Bisphenols from Diet and Cosmetics - The Human Biomonitoring Study from the EU Project Euromix

Author(s): Monica Andreassen, Cecile Karrer, Natalie von Goetz, Amrit K. Sakhi, Hubert Dirven and Trine Husøy
Published in: 2018

Developing PBPK/PD model to characterize the mixture effect of TCDD and DEHP altering estradiol kinetic in ovary via crosstalk mechanism

Author(s): Sharma, R. P., Schuhmacher. M. Kumar V.,
Published in: 2016

Real-Life Exposure to Mixtures of Chemicals in the Euromix Human Biomonitoring Study: Results from Repeated 24-Hour Diaries Reporting the Use of Personal Care Products

Author(s): Monica Andreassen, Hege Hjertholm, Hubert Dirven and Trine Husøy
Published in: Toxicologist Database, Issue Toxicologist Database, 2018, Page(s) Society of Toxicology

PACEM. Shiny beta version 0.9.

Author(s): Karrer, Cecile; von Goetz, Natalie; Hungerbühler, Konrad; Bokkers, Bas; Delmaar, Christiaan
Published in: 2019

Deliverable 10.1 – Website for EuroMix project

Author(s): Gunnlaugsdóttir, H; Jensen, S
Published in: Issue 1, 2015
DOI: 10.5281/zenodo.1066786

Deliverable 1.2 - Data management plan

Author(s): van Klaveren, J; Sprong, C; Jongenelen, J; Husøy, T; Dirven, H; Peijnenburg, A
Published in: Issue 1, 2016
DOI: 10.5281/zenodo.1064629

Deliverable 10.3 - Plan for the dissemination and exploitation of the results from EuroMix

Author(s): Gunnlaugsdóttir, H; Jensen, S; van Klaveren, J; Zilliacus, J; Durinck, S
Published in: Issue 1, 2016
DOI: 10.5281/zenodo.1066887

Deliverable 10.2 - Informative poster and booklet/brochure

Author(s): Gunnlaugsdóttir, H; Jensen, S; Gylfadóttir, K; van Klaveren, J; Sporing, C; Hart, A; Nadal, M; Torrente, M; Garcia, T
Published in: Issue 1, 2016
DOI: 10.5281/zenodo.1066863

Deliverable 9.1 - Report on mixtures and implementation strategy in Europe – Assessment of chemical mixtures under consideration of current and future regulatory requirements and scientific approaches

Author(s): Rotter, S; Beronius, A; Hanberg, A; Zilliacus, J; Nikolopoulou, D; Machera, K; Solecki, R
Published in: Issue 1, 2016
DOI: 10.5281/zenodo.1067585

Deliverable 6.1 - Demonstration prototype of the EuroMix model toolbox

Author(s): van der Voet, H; de Boer, W; Kruisselbrink, J; van Lenthe, M; Crépet, A; Kennedy, M; Sprong, C; van Klaveren, J
Published in: Issue 1, 2016
DOI: 10.5281/zenodo.1066087

Deliverable 2.1 - Report describing cumulative assessment groups for a broad range of chemicals, based on information extracted from (literature) databases

Author(s): Kyriakopoulou, K; Nikolopoulou, D; Machera, K; Peijnenburg, A; Louca‐ Christodoulou, D; Hadjiloizou, P; Beronius, A; Håkansson, H; Hanberg, A; Eberini, I; Rorije, E
Published in: Issue 1, 2016
DOI: 10.5281/zenodo.1065327

Deliverable 1.1 – Gender Plan

Author(s): van Klaveren, J; Sprong, C
Published in: Issue 1, 2016
DOI: 10.5281/zenodo.1064620

Elicitation Tool 3

Author(s): Kennedy, Marc; Hart, Andrew; Roelofs, Victoria; Roelofs, Willem
Published in: 2018
DOI: 10.5281/zenodo.1243619

Relative potency ranking of azoles altering cranio-facial morphogenesis in rat: an in vitro data modelling approach

Author(s): M. Battistoni, F. Di Renzo, F. Metruccio, A. Moretto, E. Menegola
Published in: Toxicology Letters, Issue 295, 2018, Page(s) S193, ISSN 0378-4274
DOI: 10.1016/j.toxlet.2018.06.868

PBPK/PD coupled HPG SB model to analyze the reproductive toxicity of EDs: Case study on mixture effects of DEHP and TCDD

Author(s): R.P. Sharma, M. Schuhmacher, V. Kumar
Published in: Toxicology Letters, Issue 295, 2018, Page(s) S249, ISSN 0378-4274
DOI: 10.1016/j.toxlet.2018.06.1023

Concentration-response analysis of data obtained in mouse foetuses exposed in utero at E8 to azole antifungals (cyproconazole and triadimefon) alone or in mixture

Author(s): Elena Menegola, Francesca Metruccio, Maria Battistoni, Francesca Di Renzo, Angelo Moretto
Published in: Reproductive Toxicology, Issue 80, 2018, Page(s) 21, ISSN 0890-6238
DOI: 10.1016/j.reprotox.2018.06.080